One example of an antithrombosis approach is a method that inhibits the enzyme activity of thrombin. Compounds having an antagonistic effect on thrombin receptors are recently anticipated to exert a prominent effect in the treatment and prevention of diseases in which thrombin is involved, for example, thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart diseases, disseminated intravascular coagulation syndrome, hypertension, inflammatory diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disorders, and malignant tumors. Therefore, thrombin receptor antagonists that satisfy points such as pharmacological activity, specificity for thrombin receptors, safety, dose, and oral effectiveness are needed.
2-Iminopyrrolidine derivatives and salts thereof have already been found to have a prominent inhibitory activity on thrombin receptors and to be useful as thrombin receptor antagonists (Patent Document 1). Among the 2-iminopyrrolidine derivatives and salts thereof, Patent Document 1 describes methods for producing, for example, compounds having the following general formula (A1):
(wherein RA represents a C1-6 alkyl group, RB represents a C1-6 alkoxy group, and RC represents a 5-14 membered heterocyclic group), or salts thereof.
The aforementioned Patent Document 1 describes that fluorine-containing cyclic benzamidine derivatives (A2) having the following formula
may be important intermediates in the production of the aforementioned compounds A1, and further describes a method for producing fluorine-containing cyclic benzamidine derivatives (A2) using dibromofluorobenzene derivatives (A3) (Example 7 of Patent Document 1 and the like).
As a method for producing the dibromofluorobenzene derivatives (A3), the following method, for example, is disclosed (Patent Document 1, Example 7 and the like). Unless otherwise specified, “Et” represents an ethyl group in the present description.
[Patent Document 1] WO 02/085855